Fructopyranose sulfamates, compounds of Formula I, are structurally novel anti-epileptic compounds that are highly effective anticonvulsants in animal tests (Maryanoff et al., J. Med. Chem. (1987) 30:880-887; Maryanoff et al., Bioorg. Med. Chem. Lett. (1993) 3:2653-2656; Shank et al., Epilepsia (1994) 35:450-460; and Maryanoff et al., J. Med. Chem. (1998) 41:1315-1343). These compounds are covered by three U.S. Patents: U.S. Pat. No. 4,513,006, U.S. Pat. No. 5,242,942, and U.S. Pat. No. 5,384,327. One of these compounds, 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate known as topiramate, has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in treating simple and complex partial seizures and secondarily generalized seizures (Faught et al., Epilepsia (1995) 36(S4):33; Sachdeo et al., Epilepsia (1995) 36(S4):33; T. A. Glauser, Epilepsia (1999) 40(S5):S71-80; and R. C. Sachdeo, Clin. Pharmacokinet. (1998) 34:335-346), and is currently marketed for the treatment of seizures in patients with simple and complex partial epilepsy and seizures in patients with primary or secondary generalized seizures in the United States, Europe and most other markets throughout the world.
Fructopyranose sulfamates, compounds of Formula I, were initially found to possess anticonvulsant activity in the traditional maximal electroshock seizure (MES) test in mice (Shank et al., Epilepsia (1994) 35:450-460). Subsequent studies revealed that Compounds of Formula I were also highly effective in the MES test in rats. Topiramate was also found to effectively block seizures in several rodent models of epilepsy (Nakamura et al., Eur. J. Pharmacol. (1994) 254:83-89), and in an animal model of kindled epilepsy (A. Wauquier and S. Zhou, Epilepsy Res. (1996) 24:73-77).
Shank et al., in WIPO publication WO 98/00124, disclose the use of fructopyranose sulfamates, compounds of formula I, for the treatment of postischemic neurodegeneration. Further, it has been reported that topiramate has a dose- and use-dependent neuroprotective effect, when used two hours after MCA embolization in a rat model of focal ischemia (Yang et al., Brain Res. (1998) 804(2):169-76). The neuroprotective effect of topiramate against neuronal damage following global ischemia in gerbils via bilateral carotid occlusion and in rats by cardiac arrest has also been described (Lee et al., Neuroscience Let. (2000) 281(2-3):183-186; Edmonds et al., Life Sciences (2001) 69:2265-2277).
More recently, the addition of topiramate to low dose urokinase was suggested to benefit ischemic stroke treatment by improving neurological recovery, attenuating infarction size, and reducing the risk of cerebral damage (Yang et al., Neuropharm. (2000) 39(5):881-888; Yang et al., J. Neurosurg. (2000) 92(5):841-847).
R. P. Shank, in WIPO publication WO 00/61138, discloses the use of fructopyranose sulfamates, compounds of formula I, for the treatment of chronic neurodegenerative disorders. R. P. Shank, in U.S. Pat. No. 5,753,694, discloses the use of fructopyranose sulfamates, compounds of formula I, for the treatment of amyotrophic lateral sclerosis (ALS).
Recent studies showed that topiramate promotes neurite outgrowth in rat neuronal cultures and recovery of function after facial nerve crush injury in the rat. In these studies, topiramate's neurotrophic effects were dose-dependent (Smith-Swintosky et al., NeuroReport (2001) 17:1031-1034).
There is some suggestion that topiramate may impair attention in some individuals, a frequently noted side effect of anti-epileptic (L. A. Burton and C. Harden, Epilepsy Res. (1997) 27:29-32). It has also been reported that topiramate, under certain circumstances, may have a negative impact on cognition, consistent with subjective complaints of some patients (Thompson et al., J. Neuro. Neurosurg. Psych. (2000) 69(5):636-641). However, these central nervous system effects of topiramate are generally mild to moderate in severity, usually occur early in treatment (often during titration), resolve with continued treatment and are reversible (Reife et al., Epilepsia (2000) 41(Supp 1):S66-S71). Additionally, the gradual introduction of topiramate reduces the extent of cognitive impairment (Aldenkamp et al., Epilepsia (2000) 41(9):1167-1178).
Erythropoietin (EPO) is a glycoprotein hormone produced by the kidney in response to tissue hypoxia that stimulates red blood cell production in the bone marrow. The gene for erythropoietin has been cloned and expressed in Chinese hamster ovary (CHO) cells as described in U.S. Pat. No. 4,703,008. Recombinant human erythropoietin (r-HuEPO, rhEPO, Epoetin alfa) has an amino acid sequence identical to that of human urinary erythropoietin, and the two are indistinguishable in chemical, physical and immunological tests. Recombinant human erythropoietin acts by increasing the number of cells capable of differentiating into mature erythrocytes, triggering their differentiation and augmenting hemoglobin synthesis in developing erythroblasts (S. B. Krantz, Blood (1991) 77:419-434; B. S. Beckman and M. Mason-Garcia, Faseb Journal (1991) 5:2958-2964).
Epoetin alfa is approved for sale in many countries for the treatment of anemia. Epoetin alfa has other potential uses, which include, but are not limited to anemia in chronic renal failure (dialysis and pre-dialysis), anemia in zidovudine treated HIV positive patients, anemia in cancer patients receiving platinum-based chemotherapy, as a facilitator of autologous blood pre-donation, and as a peri-surgical adjuvant to reduce the likelihood of requiring allogeneic blood transfusions in patients undergoing orthopedic surgery.
EPO influences neuronal stem cells, likely during embryonic development, and possibly during in vitro experiments of differentiation (Juul et al., Pediatr. Dev. Pathol. (1999) 2(2):148-158; Juul et al., Pediatr. Res. (1998) 43(1):40-49). Further, neonates and infants that suffer CNS injury via hypoxia, meningitis, and intraventricular hemorrhage, show an EPO induced neuroprotective effect (Juul et al., Ped. Res. (1999) 46(5):543-547).
EPO helps prevent apoptosis of neural tissue in cases of insult that create hypoxia. This may de due to the local production of EPO by astrocytes and other brain cells (Morishita et al., Neuroscience (1996) 76(1):105-116). In addition, EPO could cross the blood-brain barrier in clinical conditions associated with a disruption, breakdown, or dysregulation of the barrier. Neuroprotection has been demonstrated in gerbil hippocampal and rat cerebrocortical tissue (Sakanaka et al., P.N.A.S. USA (1998) 95(8):4635-4640; Sadamoto et al., Biochem. Biophys. Res. Commun. (1998) 253(1):26-32).
EPO administration reduces brain infarct volume in mice subjected to cerebral ischemia (Bernaudin et al., J. Cereb. Blood Flow Metab. (1999) 19(6):643-51), reduces brain infarct volume in rats after middle cerebral artery occlusion (Brines et al., P.N.A.S. USA (2000) 97(19):10526-31), prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral (Sadamoto et al., Biochem. Biophys. Res. Commun. (1998) 9/253(1):26-32), reduces cortical necrotic neuron count in a rabbit model of cerebral ischemia following subarachnoid hemorrhage (Alafaci et al., Eur. J. Pharmacol. (2000) 13/406(2):219-25), and protects cortical neurons from hypoxia and AMPA toxicity (A. D. Sinor and D. A. Greenberg, Neurosci. Lett. (2000) 290(3):213-5). EPO also improves cognitive function in chronic hemodialysis patients (L. Kambova, Nephrol. Dial. Transplant. (1998) 13(1):229-30; Temple et al., Nephrol. Dial. Transplant. (1995) 10(9):1733-1738; and A. R. Nissenson, Am. J. Kidney Dis. (1992) 20(1 Supp. 1):21-24).
EPO also induces biological effects on PC12 cells including change in Ca+2, change in membrane potential, and promotion of survival after glutamate toxicity and NGF withdrawal. This has been interpreted as EPO stimulating neural function and viability (Koshimura et al., J. Neurochem. (1999) 72(6):2565-2572; Tabira et al., Int. Dev. Neurosci. (1995) 13(3/4):241-252).
EPO may also influence neuronal stem cell commitment to drive differentiation of neurons as opposed to astrocytes or oligodendrocytes. This is similar to activity of EPO, where it functions to drive commitment of hematopoietic stem cells to produce red blood cells (RBCs). CNS hypoxic injury, results in the production of EPO from astrocytes which commits neuronal stem cells to differentiate into neurons, and which exhibits a neuroprotective function for existing neurons (WIPO publication number WO 99/21966, published on May 6, 1999 by Weiss et al.).
More recently, Ehrenreich et al., in WIPO publication WO 00/35475, describe the use of erythropoietin for the treatment of cerebral ischemia, for example in stroke patients.
Brines et al., in WIPO publication WO 00/61164, describe modulation of excitable tissue function by peripheral administration of erythropoietin.
O'Brien et al., in U.S. Pat. No. 5,700,909, issued Dec. 23, 1997 (Seq. ID. No. 11), disclose a 17 amino acid peptide sequence of EPO which acts through the EPO-R to induce biological activity in NS20Y, SK-N-MC, and PC12 cells including sprouting, differentiation, neuroprotection, and prevention of neuronal cell death. This peptide (designed epopeptide AB) does not promote proliferation of hematologic cells, thus it appears inactive in erythropoietic cell lines well understood for their EPO responsiveness. When epopeptide AB was injected into the muscle of mice, the frequency of motor end plate sprouting in the adjacent muscles increased in a manner similar to that induced by ciliary neurotrophic factor. These data are interpreted within the concept that neuronal (but not hematological) cells respond to a peptide sequence within EPO and that EPO may have separate domains for neurotrophic and hematotrophic activity (Campana et al., Int. J. Mol. Med. (1998) 1(1):235-241; J. S. O'Brien in U.S. Pat. No. 5,700,909, issued Dec. 23, 1997; J. S. O'Brien in U.S. Pat. No. 5,571,787, issued Nov. 5, 1996; J. S. O'Brien in U.S. Pat. No. 5,714,459, issued Feb. 3, 1998; and J. S. O'Brien and Y. Kashimoto in U.S. Pat. No. 5,696,080, issued Dec. 9, 1997).
Zivin et al., in WIPO publication WO 96/40772, disclose peptide dimers which behave as cell surface receptor agonists in their dimeric form, including for example, peptide dimers that bind to the erythropoietin receptor and simulate its function.
Co-therapy using fructopyranose sulfamates and erythropoietin has not, however, yet been contemplated in the art.